期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 92, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.intimp.2020.107332
关键词
Valproic acid; Neuropathic pain; Neuroinflammation; Microglia; NF-kappa B
资金
- National Natural Science Foundation of China [81471858]
- Science and Technology Planning Project of Zhongnan Hospital of Wuhan University [PTXM2020012]
This study shows that VPA alleviates neuropathic pain by suppressing proinflammatory cytokines, promoting M2 microglial polarization, reducing spinal cell apoptosis, and regulating the STAT1/NF-kappa B and JAK2/STAT3 signaling pathways to modulate microglial function and suppress spinal neuroinflammation.
Spinal inflammation is a pathophysiological state of neuropathic pain (NP). The subsequent microglial activation and neuroinflammatory response are contributing factors for long-lasting behavioral hypersensitivity. Valproic acid (VPA), a histone deacetylase inhibitor, has promising anti-inflammatory and neuroprotective properties for clinical use in the treatment of neurological disorders. However, the underlying mechanisms of its effects on NP have not been determined. This study aimed to clarify the possible mechanisms by which VPA alleviates NP in rat models induced by spinal nerve ligation (SNL). Intraperitoneal injection of VPA (300 mg/kg) efficiently attenuated mechanical allodynia in rats with NP. VPA exerted anti-inflammatory effects by downregulating proinflammatory cytokines (tumor necrosis factor-a, cytokines interleukin-1 beta, cytokines interleukin-6; TNF-alpha, IL-1 beta, and IL-6) and upregulating anti-inflammatory cytokines (transforming growth factor-beta, cytokines interleukin-10, cytokines interleukin-4; TGF-beta, IL-10 and IL-4). Additionally, VPA suppressed spinal microgliosis and promoted the polarization of microglia towards the M2 phenotype to further ameliorate spinal neuroinflammation. VPA also exerted neuroprotective effects by decreasing spinal cell apoptosis. The anti-inflammatory and neuroprotective effects may have depended on changes in nuclear histone deacetylase 3 (HDAC3) expression following VPA treatment. Moreover, VPA treatment inhibited nuclear factor-kappa B (NF-kappa B) p65 nuclear expression and upregulated acetylated the signal transducer and activator of transcription 1 (STAT1). In addition, VPA suppressed SNL-induced phosphorylation of Janus Kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Taken together, our results demonstrate that VPA is a promising anti-inflammatory agent suitable for NP therapy that regulates microglial function and suppresses spinal neuroinflammation via the STAT1/NF-kappa B and JAK2/STAT3 signaling pathways.
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